Over the past 25 years, obesity and diabetes have increased to near pandemic levels. Both obesity and diabetes are characterized by a dysfunction in the central regulation of energy balance. Arcuate (ARC) glucose sensing neurons (GSNs) are ideally situated to serve as the neuronal substrate which confers the brain with the ability to sense and respond to changes in glucose levels. These neurons are regulated by the critical signals of whole body energy balance, insulin and leptin. Our data show that the nature of the insulin effect varies with extracellular glucose. Furthermore, our data implies that insulin decreases the glucose sensitivity of ARC GSNs. Fatty acids also serve as a signal of energy homeostasis in the ARC. While, the acute effects of these nutrient and hormonal signals of peripheral energy homeostasis have been examined their effects on the glucose sensitivity of ARC GSNs remains to be defined. This proposal will test the overall hypothesis that the activity/glucose sensitivity of ARC GSNs is determined by the nutrient and hormonal milieu. Furthermore, dysruption in insulin and leptin signaling seen during obesity impairs ARC GSNs. This may contribute to the dysfunctional central regulation of energy balance. [unreadable] [unreadable] [unreadable]